Patients with peripheral arterial disease (PAD) frequently have functional limitations and symptoms of claudication that impact adversely on their quality of life. Many progress to critical limb ischemia requiring revascularization. Vascular inflammation and insulin resistance are two important and interdependent conditions that are associated with atherosclerosis. Moreover, both inflammation and insulin resistance cause abnormalities in vascular function and insulin resistance interferes with skeletal muscle metabolism. As such, inflammation and insulin resistance provide attractive targets for therapy that could potentially ameliorate the development of symptomatic PAD or improve the function and clinical outcomes of patients with PAD. Accordingly, the applicants propose three specific aims to determine whether inflammation and insulin resistance contribute to the functional and clinical consequences of PAD. First, a prospective, nested, case-control evaluation will be performed to test the hypothesis that baseline plasma levels of inflammatory cytokines (e.g. interleukin (IL)-4, IL-6, IL-18, macrophage inhibiting cytokine-1, CD 40 ligand) among healthy men are associated with the development of future symptomatic PAD. Second, to test the hypothesis that inflammation and insulin resistance contribute to reduced walking distance in patients with intermittent claudication by impairing vascular reactivity and skeletal muscle metabolic function, plasma markers of inflammation and insulin resistance, endothelium-dependent and independent vasodilation (by vascular ultrasonography) and skeletal muscle glucose utilization (by [18F] FDG positron emission tomography) will be measured before and after 12 weeks of treatment with rosiglitazone, atorvastatin or placebo in a 2x2 factorial design protocol. Third, to test the hypothesis that inflammation and insulin resistance are associated with the incidence and progression of vein graft disease in patients undergoing lower extremity vein bypass, functional and morphologic changes in vein grafts (measured by ultrasound and magnetic resonance imaging) will be assessed and related to inflammation and insulin resistance and to a composite clinical outcome of graft occlusion, re-intervention or major amputation. It is anticipated that the findings from this investigation will uncover novel pathophysiologic mechanisms and foster a new paradigm for the treatment of PAD.